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Enzima mejorada para síntesis de metabolitos y fármacos

Resumen

Tipo:
Oferta Tecnológica
Referencia:
TOES20170123001
Publicado:
02/03/2017
Caducidad:
02/03/2018
Resumen:
Un centro español de investigación pública ha generado una variación proteica de la peroxigenasa del hongo Agrocybe aegerita con propiedades mejoradas de actividad catalítica, estabilidad y capacidad de expresión heteróloga. La enzima mutante ha sido diseñada para su aplicación en reacciones de hidroxilación aromática, especialmente en la síntesis de 5´-hidroxipropranolol. La enzima tiene múltiples aplicaciones en reacciones regioselectivas de síntesis orgánica con oxifuncionalización de hidrocarburos, con especial
interés en sustratos aromáticos y metabolitos humanos de fármacos. El centro busca empresas interesadas en utilizar esta enzima en la producción de metabolitos y otros fármacos bajo licencia de patente.



Details

Tittle:
Improved enzyme for metabolites and drug synthesis.
Summary:
A Spanish public research organisation has generated a proteic variation of the peroxigenase from the Agrocybe aegerita fungi, with enhanced properties of catalytic activity, stability and heterologous expression capacity. The mutant enzyme has been designed to be applied in aromatic hydroxylation reactions, especially for 5´-hydroxipropranolol synthesis. Companies interested in the use of this enzyme for the production of human drug metabolites and other drugs, under patent license, are sought.
Description:
Human drug metabolites (HDMs) are the products of the metabolic breakdown of drugs into the human body, usually carried out by the P450 liver enzymes. The measurement of the toxicity, the effectiveness and the activity of these metabolites is essential for medical and pharmaceutical industry; however, the chemical synthesis of these small molecules is complex and leads to low recoveries. In this context, the enzyme of this invention can provide a more efficient alternative process.
The oxygenase enzyme was obtained applying genetic engineering to the unspecific peroxigenase (UPO) secreted by the edible mushroom Agrocybe aegerita. Starting with the wild-type UPO, some mutations where introduced with the directed evolution technique, resulting in new mutant proteins with increased peroxygenase (mono-oxygenase) activity compared with peroxidase activity, making it ideal for being used in the selective hydroxylation process and decreasing by-products generation in the reaction medium. Moreover this new mutants can be expressed in industrial commonly used yeast, as Saccharomyces cerevisae or Pichia pastoris.
Some test reactions were carried out with the new enzyme for the synthesis of 5´-hydroxipropranolol from propranolol. The regioselectivity obtained for this compound was around 99% and the catalytic efficiency was 2 orders of magnitude higher than the values found in the wild-type UPO; leading also to an increase of the affinity for the propranolol of 5.7 times. Moreover, the mutant enzyme showed a peroxidase activity 11 times lower than the wild-type UPO, avoiding therefore the transformation of the 5´-hydroxipropranolol in the corresponding quinone, which leads to undesirable polymers and other by-products.

The Spanish research center is looking for enzyme producers or pharma-chemical companies that can be interested in the production or the use of enzyme for the synthesis of human drug metabolites or other drugs, under a patent license. The enzyme has only been tested at a laboratory scale, but it can be easily adapted to an industrial scale and can be produced in enough amounts to be applied in industrial reactors. The research center can collaborate in this kind of scale-up developments under a research cooperation agreement.

The Spanish public entity has broad experience in the development of novel catalyst for innovative industrial processes and in the development of novel enzymes using directed evolution technique.
Advantages and Innovations:
· The enzyme catalyses the production of 5´-hydroxipropranolol, without the use of antioxidants and co-factors, as the other enzymatic methods.
· The mutant can be expressed in S. cerevisiae y P. pastoris reaching levels of production up to 0.2 g/L, which is suitable for its industrial use.
· Shows a high thermal stability, with a value of Tª50 around 60º C.
· The total turnover number (TTN) is 15 times higher than the wild-type UPO, reaching a value of 45,000, similar to those enzymes commercially available.
· The catalytic efficiency for 5´-hydroxipropranolol is up to 1.3 × 106 s-1 M-1.
· The enzyme shows multiple uses in regioselective reactions for organic synthesis with oxy-functionalisation of hydrocarbons, with special interest in aromatic substrates and human drugs metabolites.
Stage of Development:
Under development/lab tested
IPs:
Patent(s) applied for but not yet granted
CommeR Statunts Regarding IPR Status:
PCT ("international") patent application filled

Partner sought

Type and Role of Partner Sought:
The Spanish research center is looking for companies interested in the enzyme and its applications in chemical synthesis, they can be enzyme producers or pharma companies. The collaboration consider is a License Agreement for the use of the enzyme. Additionally, research cooperation agreements could be considered, since the industrial application of the enzyme needs some developments regarding to the scale-up.

Client

Type and Size of Client:
R&D Institution
Already Engaged in Trans-National Cooperation:
No
Languages Spoken:
English
Spanish

Keywords

Technology Keywords:
06006012 Bioprocesos
06002004 Ingeniería de proteínas
06001015 Productos farmacéuticos / medicamentos
06002003 Tecnología de enzimas